Diuretic combinations of hydrochlorothiazide and ethacrynic acid



United States Patent 3,476,858 DIURETIC COMBINATIONS 0F HYDROCHLORO- THIAZIDE AND ETHACRYNIC ACID Carl E. Nelson, Doylestown, John E. Baer, Ambler, and Elwood L. Foltz, Villanova, Pa., assignors to Merck & Co., Inc., Railway, N.J., a corporation of New Jersey N0 Drawing. Continuation-impart of application Ser. No. 342,218, Feb. 3, 1964. This application Dec. 7, 1966, Ser. No. 599,733

Int. Cl. A61k 27/00 U.S. Cl. 424246 1 Claim ABSTRACT OF THE DISCLOSURE Hydrochlorothiazide and ethacrynic acid are combined for coadministration to obtain a diuresis in excess of what can be accounted for by the activity of either one alone. For the hydrochlorothiazide may be substituted other similar benzothiadiazines. For the ethacrynic acid may be substituted other similar phenoxyacetic acids.

This invention relates to therapeutic preparations for use as diuretic agents and more particularly, it relates to preparations containing a novel combination of coacting pharmacotherapeutic agents having enhanced diuretic action.

Compounds of the benzothiadiazine class, such as chlorothiazide, are well known diuretic agents; they also have anti-hypertensive properties. The activities of the thiazides spread over a wide range, but if their respective dosage is kept in mind, the thiazide compounds are comparably effective as diuretic agents and can be used interchangeably. However, all of the thiazides have essentially the same limitations or ceilings on the urinary volume and the amount of electrolyte that can be excreted regardless of dose, and this ceiling cannot be enhanced by combinations of, or alternate use of, dififerent diuretic agents within this class.

It is an object of this invention to provide a diuretic composition which in unit dosage form will show an enhancement of urinary volume and electrolyte excretion over that obtainable with benzothiadiazine diuretics alone. Accordingly, it has now been discovered that by administering a combined dosage of diuretic agents for therapeutic administration, comprising in unitary form such as tablets, powders, capsules, syrups, and the like (1) a benzothiadiazine compound and (2) a phenoxyacetic acid compound, having diuretic action, a greatly increased diuretic effect is brought about with a minimal dosage of each of the components. The increased diuretic eifect caused by the concurrent administration of this combination is attributed to a synergism between the two types of diuretic agents. Thus, it is possible to use the minimal clinical dose of each of the components and obtain increased therapeutic benefits.

These compositions upon administration possess enhanced diuretic, natriuretic and chloruetic properties and are therefore useful in the treatment of many ailments resulting from an excessive retention of electrolytes especially sodium, chloride or sodium and chloride ions, as in the treatment of hypertension, edema and other conditions associated with electrolyte and fluid retention. These compositions also can be used to increase urine flow.

The benzothiadiazine class of compounds employed in the composition of this invention are known in the art to possess a common chemical structure. The benzothiadiazine compounds which are utilized in the composition of the present invention and their amounts in a unit dose are:

3,476,858 Patented Nov. 4, 1969 Table I Mg. (a) Chlorothiazide 200-500 (b) Flumethiazide 200-500 (c) Trichloromethiazide 2-5 (d) Cyclopenthiazide .20-.50 (e) Hydrochlorothiazide 20-50 (f) Hydrofiumethiazide 20-50 (g) Benzthiazide 20-50 The second component of the synergistic combination of diuretic compounds of the present invention comprises the phenoxy acetic acid compounds described in Belgium Patents 612,755 and 624,749, published on July 17, 1962, and May 13, 1963 respectively. From 25 to 50 mg. of one of the following is put in a unit dose.

Table II (h) Ethacrynic acid.

(i) 3 chloro 4 (2 methylenebutyryl) phenoxy acetic acid.

(j) 2,3 dimethyl 4 (2 methylenebutyryl) phenoxy acetic acid.

(k) 2,3 dichloro 4 (2 ethylidenebutyryl) phenoxy acetic acid.

The above two tables give the amounts of each drug to go in a unit dose. From one to four such unit doses would be taken daily, multiple doses being spread over the day.

A statistical analysis of the results of one study which was carried out using three different daily dosage regimens on normal subjects (1) 100 mg. alone of ethacrynic acid (2) 100 mg. alone of hydrochlorothiazide, and (3) a combination of 50 mg. of each of these two compounds showed that there was a significant increase in urinary volume and a highly significant increase in sodium and chloride excretion when the combination of fractional quantities of the two drugs was used, as compared with that to be expected from administering each of the two drugs separately. The urine was collected for two hour periods before drug, up to eight hours after drug with a controlled water and electrolyte intake, and after a meal.

In this study the time-response curves for the two drugs used alone at a dose of 100 mg. showed differential response with time. Ethacrynic acid showed a more rapid excretion of urine and electrolytes initially, while hydrochlorothiazide showed a more sustained response. The combination of fractional dosages showed larger excretion values at 2 to 4 hours after administration of the drug than the average excretion values for the two drugs used alone. This was significant statistically for all four parameters measured, namely urine volume, sodium, chloride and potassium. The effect was least for potassium excretion. Unexpectedly higher values were also observed in the two hour collection period post-meal. However, the variability in response was much higher in this period and the differences were significant only at a 0.05 level of probability. Significant differences were shown for all parameters except potassium. The total excretion for the controlled intake eight hour period post drug were higher for the combination than the average total excretions for the two drugs used alone. This effect was significant for volume, and highly significant for sodium and chloride.

Synergism can likewise be demonstrated with other fractional combinations of equipotent doses of ethacrynic acid and hydrochlorothiazide. Thus, instead of approximately a 50%50% fractional combination of each drug, a %-25% or a 25%-75% combination may be employed. Moreover, the equipotent doses may be selected at a high level of response, at a medium level of response, or at a low level of response, depending upon the age and weight of the patient to be treated and upon the particular ailment to be treated.

At the lower dose levels, hydrochlorothiazide appears to be more potent than ethacrynic acid, but at the higher dose levels, the reverse seems to be true, namely, hydrochlorothiazide appears to be less potent than ethacrynic acid.

The following examples are illustrative of representative formulations contemplated by the present invention but are not to be construed as limiting the invention. Various inert materials may be incorporated into the formulations disclosed herein without departing from the scope of the invention as described in the appended claim. The drugs may also be administered intravenously as well as orally.

Example 1.Compressed tablets weighing 275 mg. containing ethacrynic acid and hydrochlorothiazide (a) 50 mg. of ethacrynic acid and 50 mg. of hydrochloro thiazide per tablet:

Per tablet, mg.

(b) 40 mg. of ethacrynic acid and 50 mg. of hydrochlorothiazide per tablet:

Per tablet, mg.

Ethacrynic acid 40.0 Hydrochlorothiazide 50.0 Lactose USP powder 70.0 Calcium sulfate 85.0 Corn starch 27.4 Magnesium stearate 2.6

25 mg. of ethacrynic acid and 20 mg. of hydrochlorothiazide per tablet:

Per tablet, mg.

Ethacrynic acid 25.0 Hydrochlorothiazide 20.0 Lactose USP powder 115.0 Calcium sulfate 85.0 Corn starch 27.4 Magnesium stearate 2.6

Directions for preparing the above compressed tablets The ethacrynic acid, hydrochlorothiazide, lactose and calcium sulfate are mixed together for five minutes, then reduced to a No. 90 mesh powder, and remixed for five minutes. The powders are then granulated with starch paste, passed through a screen and dried at 130 F. After drying, the granulation is further reduced to approximately a No. 16 mesh granule. The corn starch is passed through a No. 60 bolting cloth onto the granulation and mixed for five minutes. The magnesium stearate is passed through a No. 60 bolting cloth onto the granulation and blended. The material is then compressed into tablets.

Example 2.Enteric coated tablets containing ethacrynic acid and hydrochlorothiazide with 1000 mg. of potassium chloride per tablet (a) 50 mg. of ethacrynic acid and 50 mg. of hydrochlorothiazide per tablet:

Per tablet, mg.

Ethacrynic acid 50.0 Hydrochlorothiazide 50.0 Potassium chloride 1000.0 Stearic acid 4.0 Enteric coating 45.0 Film coating 25.0

(b) 40 mg. of ethacrynic acid and 50 mg. of hydrochlorothiazide per tablet:

Per tablet, mg.

Ethacrynic acid 40.0 Hydrochlorothiazide 50.0 Potassium chloride 1000.0 Stearic acid 4.0 Calcium phosphate dibasic 10.0 Enteric coating 45.0 Film coating 25.0

(c) 25 mg. of ethacrynic acid and 20 mg. of hydrochlorothiazide per tablet:

Per tablet, mg.

Directions for preparing the above enteric coated tablets The hydrochlorothiazide and ethacrynic acid are mixed thoroughly for five minutes, reduced to a N0. mesh powder and remixed for five minutes. The potassium chloride and calcium phosphate dibasic (if needed) are then added and mixed for ten minutes. Finally, the stearic acid is passed through a No. 90 bolting cloth onto the granulation and the mixture compressed into tablets.

The compressed tablets are placed into a coating pan of special shape and an enteric coating solution containing cellulose acetate phthalate and diethyl phthalate in acetone is applied by spraying. When the prescribed quantity of enteric coating is applied, the tablets are moved from the pan and dried at ISO- F. in an oven. After completion of the drying cycle, the tablets are returned to the coating pan and a film coating is applied by way of a spraying technique. The tablets undergo another drying step at l30-140 F. after which they are allowed to cool and are polished by revolving in a wax-coated pan.

Example 3.Dry-filled capsules weighing 400 mg. each containing ethacrynic acid and hydrochlorothiazide (a) 50 mg. of ethacrynic acid and 50 mg. of hydrochlorothiazide per capsule:

Per capsule, mg.

Ethacrynic acid 50.0 Hydrochlorothiazide 50.0 Lactose USP 296.0 Magnesium stearate USP 4.0

(b) 40 mg. of ethacrynic acid and 50 mg. of hydrochlorothiazide per capsule:

Per capsule, mg.

Ethacrynic acid 40.0 Hydrochlorothiazide 50.0 Lactose USP 306.0 Magnesium stearate USP 4.0

(c) 25 mg. of ethacrynic acid and 20 mg. of hydrochlorothiazide per capsule:

Per capsule, mg.

Ethacrynic acid 25.0 Hydrochlorothiazide 20.0 Lactose USP 351.0 Magnesium stearate USP 4.0

Directions for preparing the above dry-filled capsules Example 4.Syrup containing ethacrynic acid and hydrochlorothiazide (a) 50 mg. of ethacrynic acid and 50 mg. of hydrochlorothiazide per 5 cc.:

Per 5 cc.

Ethacrynic acid mg. 50 Hydrochlorothiazide mg. 50 Sorbitol solution percent 15 Tragacanth do 0.4 Sorbic acid do 0.05 Benzoic acid do 0.15 Saccharin sodium do 0.025 Cyclamate sodium (cyclohexanesulfamic acid) -do 0.05 Ethyl alcohol 95% do 1.5 Flavors, q.s. Dye, q.s. Deionized water, q.s cc 5.0

(b) 40 mg. of ethacrynic acid and 50 mg. of hydrochlorothiazide per cc.:

Per 5 cc.

Ethacrynic acid mg.-- 40 Hydrochlorothiazide mg. 50 Sorbitol solution percent 15 Tragacanth do 0.4 Sorbic acid do- 0.05 Benzoic acid do 0.15 Saccharin sodium do 0.025 Cyclamate sodium (cyclohexanesulfamic acid) do 0.05 Ethyl alcohol 95% do 1.5 Flavors, q.s. Dye, q.s. Deionized water, q.s cc 5.0

(c) 25 mg. of ethacrynic acid and 20 mg. of hydrochlorothiazide per 5 cc.:

Per 5 cc. Ethacrynic acid mg. 25 Hydrochlorothiazide mg. 20 Sorbitol solution percent 15 Tragacanth do 0.4 Sorbic acid do 0.05 Benzoic acid do 0.015 Saccharin sodium do 0.025 Cyclamate sodium (cyclohexanesulfamic acid) do 0.05

Per 5 cc. Ethyl alcohol do 1.5 Flavors, q.s. Dye, q.s. Deionized water, q.s. cc 5.0

Directions for preparing the above formulated syrups (l) Disperse the tragacanth in water. Allow gel to hydrate overnight.

(2) Dissolve the sodium saccharin and sodium cyclamate in water and add to the sorbitol solution.

(3) Combine the syrup and tragacanth gel.

(4) Dissolve the benzoic acid, sorbic acid, and flavors in the ethyl alcohol 95% and add to the suspension.

(5) Dissolve the dye in water and add to the suspension.

(6) Disperse the hydrochlorothiazide and ethacrynic acid in the suspension and bring the product to total volume with deionized water.

(7) Process the product through an homogenizer.

Example 5.Solution for intravenous injection containing ethacrynic acid and hydrochlorothiazide The following is a formula for one liter of bulk solution prior to lyophilization:

Hydrochlorothiazide g 10.50

Ethacrynic acid g 10.30

Mannitol g 20.00

Thimerosal g 0.02

Sodium hydroxide g 3 4.00

(q.s. pH 10.5)

Water for injection ml. 1,000.0

Includes 5% excess.

2 Includes 3% excess.

3 Approximate.

The hydrochlorothiazide and ethacrynic acid are suspended in about 800 ml. of water for injection. The sodium hydroxide (l N) is added to the mixture until solution is complete and the alkalinity is approximately pH 10.5. The mannitol and Thimerosal are dissolved, and the pH is determined and then adjusted, if necessary, to pH 10.5 with sodium hydroxide solution (1 N). The volume is adjusted to one liter with additional water for injection. The solution is sterilized by filtration through a sterile Selas filter (015 candle). The filtrate is subdivided asceptically into 10 ml. vials, filling 5.0 ml. per vial. The vials with content are frozen and lyophilized. The theoretical yield is 200 vials, each vial having the following contents:

Per vial, mg.

Hydrochlorothiazide 50.0 Ethacrynic acid 50.0 Mannitol 100.0 Thimerosal 0.1 Sodium hydroxide 20.0

Thimerosal is sodium ethylmercurithiosalicylate, which has the formula:

(IJOONa In all of the above examples other fractional combinations of equipotent submaximal doses of ethacrynic acid and hydrochlorothiazide may be employed. Likewise the synergistic combination of ethacrynic acid and hydrochlorothiazide may be replaced by other synergistic combinations of drugs selected from Table 1 and Table 2 as heretofore described, without departing from the scope of the invention as defined in the appended claim.

What is claimed is:

1. A pharmaceutical preparation for inducing diuresis 7 in a host requiring diuresis which comprises a combination selected from the group consisting of:

(a) about 20 mg. of hydrochlorothiazide and about 25 mg. of ethacrynic acid, and

mg. of ethacrynic acid.

References Cited UNITED STATES PATENTS 3,137,625 6/1964 Biel.

8 OTHER REFERENCES Wilson et al., British Medical Journal, Feb. 2, 1963, pp. 285-292.

Schultz et al., Journal of Med. and Pharm. Chem., vol. 5, pp. 660-662 (1962).

American Druggist, vol. 147 (5), p. 35, Mar. 4, 1963.

ALBERT T. MEYERS, Primary Examiner 1 STANLEY J. FRIEDMAN, Assistant Examiner 

